Safe and efficient delivery of nucleic acid constructs to target cells has great potential for the treatment of genetic diseases (Mancuso, et al. Nature, 2009, 461, 784-8; Waehler, et al. Nature Rev. Genet., 2007, 8, 573-587; Semple, et al. Nature Biotech, 2010, 20, 172-6; and Davis, et al. Nature, 2010, 464, 1067-70). However, the clinical success of this approach depends on the development of effective delivery vehicles with low toxicity. Viral and non-viral vectors both have been studied for this purpose, but suffer from several key limitations. Although efficient and persistent, viral vectors are challenged by issues of large-scale production, immunogenicity, and safety, whereas non-viral vectors are limited primarily by lack of efficiency. Nonetheless, non-viral nucleic acid delivery has attracted considerable attention due to its scalability and modest host immunogenicity compared to viral vectors (Nayak, et al. Gene Ther., 2010, 464, 1067-70; Li, et al. J. Control. Rel. 2007, 123, 181-3; and Xu, et al. J. Pharm. Sci., 2011, 38-52).
RNA interference (RNAi) is a post-transcriptional gene silencing mechanism arising from degradation or translation arrest of target RNA. The ability of 21-23 nucleotide RNAs (siRNA) to mediate RNAi in mammalian cells has enormous therapeutic potential for the treatment of viral infections, cancer and neurological disorders (Ryther, et al., Gene Therapy 2005, 12, 5). The use of siRNA has several advantages over conventional chemotherapy in that the high specificity nucleic acid drug acts “upstream” from chemotherapeutic agents conferring the ability to target any protein and the capacity to potentially evade drug resistance (Whitehead, et al., Nature Rev. Drug. Disc. 2009, 8, 129). Thus, there is an ongoing need for a safe and efficient delivery of siRNA specifically to target cells.